title: Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza.
abstract: BACKGROUND
  Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds.
  
  
  RESULTS
  By extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (d(N)/d(S)), we found the average d(N)/d(S) across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of d(N)/d(S) values for each subtype on a site-by-site basis indicated that the elevated d(N)/d(S) on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint.
  
  
  CONCLUSIONS
  Our results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution.
authors.affiliation: Institute for Evolutionary Biology, University of Edinburgh, Ashworth Building, West Mains Road, Edinburgh EH9 3JT, Scotland, UK. melissa.ward@ed.ac.uk.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Ward
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Lycett
authors.forename: Dorita
authors.initials: D
authors.lastname: Avila
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bollback
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Leigh Brown
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D005075:Biological Evolution; D001717:Birds; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000378:metabolism; D009980:Influenza A virus / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D005585:Influenza in Birds / Q000821:virology; D009439:Neuraminidase / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D016865:Reassortant Viruses / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D013269:Stochastic Processes
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C109963:hemagglutinin, avian influenza A virus; D009439:Neuraminidase